The underlying biochemical defect of Usher syndrome type II (USH2), a combined hearing loss, retinitis pigmentosa, and vestibular dysfunction, is unknown. However, it is presumed to be related to a fundamental mechanism which translates stimulus energy into electrical signals within the affected cells. We hypothesize that the USH2 gene codes for a protein that plays an important role in a basic membrane signaling process common in the cochlear and retina cells. The USH2 gene has been mapped between D1S81/PPOL and D1S70 in the chromosome 1q32-42 region. There are no other DNA polymorphims nor candidate genes in the region. We intend to clone the USH2 gene on the basis of its map position. The proposed approach involves constructing chromosome 1 specific NotI linking and jumping libraries, performing chromosomal "jumps" from PPOL and D1S81 and constructing a physical map of the region. Once the chromosomal "jumps" bring us dose to the USH2 gene, as verified by linkage analysis, we will recover the DNA sequences around the putative USH2 gene as DNA fragments cloned into yeast artificial chromosomes (YAC). YAC libraries will be screened by the NotI linking and jumping clones and the YAC clones will be connected to each other to form an array of overlapping cloned human DNA fragments. We will identify transcribed sequences, candidate genes in the region-specific YACs. Genomic DNA and YACs will be tested for the presence of hypomethylated CpG islands and evolutionary conserved sequences. The USH2 gene will be identified among the candidate genes on the basis of its tissue specific expression and consistency of mutations in affected individuals.